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DOI: 10.1055/s-0032-1317554
Development of a Scalable Synthesis of a VEGFR Inhibitor
Publication History
Received: 27 September 2012
Accepted after revision: 19 October 2012
Publication Date:
16 November 2012 (online)
Abstract
Process development and salt selection for a novel VEGFR inhibitor are described. The overall convergent synthesis involved coupling of three key fragments, 2-chloronicotinoyl chloride, 4-isopropyl-3-methylaniline and 7-aminoisoquinoline. A cost-effective and scalable synthesis of 7-aminoisoquinoline was also achieved. A transition-metal-free SNAr process enabled the final C–N coupling to afford the target molecule. A phosphate form of the drug substance with improved physical properties was selected for further development and the corresponding crystallization process was subsequently developed. Overall, a robust six-step route was developed and demonstrated on multikilogram scales affording the target compound in >30% yield and high purity (>99%).
Supporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
- Supporting Information
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